Heavy alcohol (ETOH) use affects both liver and brain. Its effects on brain may be aggravated by associated hepatic and metabolic disturbances, including insulin resistance, oxidative stress, and mitochondrial dysfunction. The proposed study will investigate effects of ETOH consumption on HIV-associated brain dysfunction. The study incorporates state-of-the-art brain imaging methods along with clinical and laboratory methods to assess interactive effects of HIV infection, ETOH consumption, and hepatic dysfunction. We will examine how neurocognitive outcome and structural brain changes vary as a function of ETOH consumption, the extent of specific metabolic disturbances, and HIV-associated factors. A longitudinal experimental design will be employed with statistical modeling methods to characterize changes over time. Recent data from our laboratory point to alcohol-associated effects of HIV in the brain, including evidence that people who consume large quantities of ETOH have greater deficits at baseline and greater change over time than non users. Furthermore, our data suggest that basal ganglia, hippocampal, and cortical volume loss occur at an accelerated rate as a function of the interaction of these factors. Diffusion tensor imagining (DTI) data provide evidence of reduced structural integrity of subcortical systems that appears to be evident prior to development of structural changes on traditional MRI. Magnetic resonance spectroscopy (MRS) findings point to both increased brain metabolite levels reflecting inflammatory processes and also neuronal damage, particularly in the basal ganglia, but also in white matter and cortical areas. These abnormalities in the brain have been linked to both HIV and ETOH, though how these two factors interact over time to cause changes in brain structure and function is not well understood. The proposed study will compare HIV-infected and seronegative control patients who have been stratified into three groups based oh their ETOH use (Heavy ETOH use, moderate ETOH use, no-ETOH) who are assessed over 36 months on neurocognitive, neuroimaging, and laboratory measures. All will undergo laboratory testing including assessment of CD4, viral load, activated macrophages from plasma and CSF, and measures of liver, insulin, and metabolic function. Neuroimaging, laboratory, and neurocognitive assessment will be conducted at baseline, 12 and 36 months. Results will inform us about the interaction of ETOH and HIV in the brain, and provide metrics for assessing structural and metabolic brain changes, potentially extending the clinical application ofthese methods for brain disorders that may lead to neurodiagnostic advances for patients with HIV, including methods for dissociating effects of HIV from other co-morbid factors, most notably ETOH consumption and liver disease.